Project Summary Coronavirus Disease of 2019 (COVID-19) is a US and global public health crisis. It has led to the deaths of, at the point of writing this application, over 476,000 patients and 10 million infected individuals worldwide. The US was the most affected country, with over 123,000 deaths thus far and over 2.4 M infections. COVID-19 is caused by a novel beta-coronavirus (CoV) known as Severe Acute Respiratory Syndrome (SARS)-CoV-2, which was reported to cause severe pneumonia and lethal respiratory failure. There is no vaccine or FDA-approved drugs for COVDI-19, and there is very little knowledge about this new virus at the basic science level. Thus, animal and cellular models are urgently needed to start to investigate the disease mechanism or test therapeutic interventions. Here, we propose to explore essential aspects of understanding COVID-19 viral infection: tissue tropism of the virus and antiviral innate immune responses of the host. Firstly, we will test viral tropism in various tissues relevant to reported COVID-19 symptoms and establish cellular models of the disease, by determining the expression of COVID-19 suggested entry receptor/cofactors, ACE2 and TMPRSS2, in various cell types and monitor the progress of infection over time using virus-specific assays and viral load quantification techniques. Secondly, we will test host cellular responses to SARS-CoV2 infection by determining the expression levels during infection, of proinflammatory cytokines and type-I interferons involved in antiviral defenses. We will also assess autophagy flux during infection, given that viruses gain growth advantage in cells by hijacking autophagy.